Survival In Several Types Of Cancer Research Articles

Pan-cancer analysis reveals GGPS1 plays an important role in tumorigenesis in multiple tumor types

The deletion of geranylgeranyl diphosphate synthase 1 (GGPS1) has been reported to inhibit the proliferation of multiple cells. Although emerging evidence has demonstrated a correlation between GGPS1 and cancer, no pan-cancer analysis has been conducted to date. This study explored the potential tumorigenesis of GGPS1 using data from the cancer genome atlas human clinical database. GGPS1 expression was considerably upregulated at both the RNA and protein levels in several cancer types, especially in breast carcinoma (BRCA), (liver) hepatocellular carcinoma (LIHC/HCC) and lung adenocarcinoma (LUAD). Amplification is the most common form of genetic alteration observed in invasive BRCA, ovarian epithelial tumor and HCC. Additionally, elevated GGPS1 expression was markedly related to poor patient prognosis and overall survival in several cancer types including LIHC. GGPS1 expression was also linked to cancer-associated fibroblasts (CAFs) infiltration in several cancer types, such as BRCA and LUAD. Moreover, GGPPS-interacting proteins and GGPS1-correlated genes in cancers were functionally enriched in terpenoid backbone biosynthesis, steroid biosynthesis, and metabolic pathways. These results indicate that GGPS1 may play a role in promoting the tumorigenesis and tumor development, particularly in BRCA and LUAD, and may play a role in steroid biosynthesis and metabolic pathways.

Socioeconomic Disparities in Six Common Cancer Survival Rates in South Korea: Population-Wide Retrospective Cohort Study.

In South Korea, the cancer incidence rate has increased by 56.5% from 2001 to 2021. Nevertheless, the 5-year cancer survival rate from 2017 to 2021 increased by 17.9% compared with that from 2001 to 2005. Cancer survival rates tend to decline with lower socioeconomic status, and variations exist in the survival rates among different cancer types. Analyzing socioeconomic patterns in the survival of patients with cancer can help identify high-risk groups and ensure that they benefit from interventions. The aim of this study was to analyze differences in survival rates among patients diagnosed with six types of cancer-stomach, colorectal, liver, breast, cervical, and lung cancers-based on socioeconomic status using Korean nationwide data. This study used the Korea Central Cancer Registry database linked to the National Health Information Database to follow up with patients diagnosed with cancer between 2014 and 2018 until December 31, 2021. Kaplan-Meier curves stratified by income status were generated, and log-rank tests were conducted for each cancer type to assess statistical significance. Hazard ratios with 95% CIs for any cause of overall survival were calculated using Cox proportional hazards regression models with the time since diagnosis. The survival rates for the six different types of cancer were as follows: stomach cancer, 69.6% (96,404/138,462); colorectal cancer, 66.6% (83,406/125,156); liver cancer, 33.7% (23,860/70,712); lung cancer, 30.4% (33,203/109,116); breast cancer, 91.5% (90,730/99,159); and cervical cancer, 78% (12,930/16,580). When comparing the medical aid group to the highest income group, the hazard ratios were 1.72 (95% CI 1.66-1.79) for stomach cancer, 1.60 (95% CI 1.54-1.56) for colorectal cancer, 1.51 (95% CI 1.45-1.56) for liver cancer, 1.56 (95% CI 1.51-1.59) for lung cancer, 2.19 (95% CI 2.01-2.38) for breast cancer, and 1.65 (95% CI 1.46-1.87) for cervical cancer. A higher deprivation index and advanced diagnostic stage were associated with an increased risk of mortality. Socioeconomic status significantly mediates disparities in cancer survival in several cancer types. This effect is particularly pronounced in less fatal cancers such as breast cancer. Therefore, considering the type of cancer and socioeconomic factors, social and medical interventions such as early cancer detection and appropriate treatment are necessary for vulnerable populations.

Pan-cancer analyses of senescence-related genes in extracellular matrix characterization in cancer

PurposeThe aged microenvironment plays a crucial role in tumor onset and progression. However, it remains unclear whether and how the aging of the extracellular matrix (ECM) influences cancer onset and progression. Furthermore, the mechanisms and implications of extracellular matrix senescence-related genes (ECM-SRGs) in pan-cancer have not been investigated.MethodsWe collected profiling data from over 10,000 individuals, covering 33 cancer types, 750 small molecule drugs, and 24 immune cell types, for a thorough and systematic analysis of ECM-SRGs in cancer.ResultsWe observed a significant correlation between immune cell infiltrates and Gene Set Variation Analysis enrichment scores of ECM-SRGs in 33 cancer types. Moreover, our results revealed significant differences in immune cell infiltration among patients with copy number variations (CNV) and single nucleotide variations (SNV) in ECM-SRGs across various malignancies. Aberrant hypomethylation led to increased ECM-SRGs expression, and in specific malignancies, a connection between ECM-SRGs hypomethylation and adverse patient survival was established. The frequency of CNV and SNV in ECM-SRGs was elevated. We observed a positive correlation between CNV, SNV, and ECM-SRGs expression. Furthermore, a correlation was found between the high frequency of CNV and SNV in ECM-SRGs and poor patient survival in several cancer types. Additionally, the results demonstrated that ECM-SRGs expression could serve as a predictor of patient survival in diverse cancers. Pathway analysis unveiled the role of ECM-SRGs in activating EMT, apoptosis, and the RAS/MAPK signaling pathway while suppressing the cell cycle, hormone AR, and the response to DNA damage signaling pathway. Finally, we conducted searches in the “Genomics of Drug Sensitivity in Cancer” and “Genomics of Therapeutics Response Portal” databases, identifying several drugs that target ECM-SRGs.ConclusionsWe conducted a comprehensive evaluation of the genomes and immunogenomics of ECM-SRGs, along with their clinical features in 33 solid tumors. This may provide insights into the relationship between ECM-SRGs and tumorigenesis. Consequently, targeting these ECM-SRGs holds promise as a clinical approach for cancer treatment.

Reactivation of telomerase reverse transcriptase expression in cancer: the role of TERT promoter mutations.

Telomerase activity and telomere elongation are essential conditions for the unlimited proliferation of neoplastic cells. Point mutations in the core promoter region of the telomerase reverse transcriptase (TERT) gene have been found to occur at high frequencies in several tumour types and considered a primary cause of telomerase reactivation in cancer cells. These mutations promote TERT gene expression by multiple mechanisms, including the generation of novel binding sites for nuclear transcription factors, displacement of negative regulators from DNA G-quadruplexes, recruitment of epigenetic activators and disruption of long-range interactions between TERT locus and telomeres. Furthermore, TERT promoter mutations cooperate with TPP1 promoter nucleotide changes to lengthen telomeres and with mutated BRAF and FGFR3 oncoproteins to enhance oncogenic signalling in cancer cells. TERT promoter mutations have been recognized as an early marker of tumour development or a major indicator of poor outcome and reduced patients survival in several cancer types. In this review, we summarize recent findings on the role of TERT promoter mutations, telomerase expression and telomeres elongation in cancer development, their clinical significance and therapeutic opportunities.

Oncogenic role and drug sensitivity of ETV4 in human tumors: a pan-cancer analysis.

Increasing evidence supports a relationship between E twenty-six variant transcription factor 4 (ETV4) and several cancers, but no pan-cancer analysis has been reported. The present study surveyed the effects of ETV4 on cancer using RNA sequencing data obtained from The Cancer Genome Atlas and GTEx, and further explored its role in drug sensitivity using data from Cellminer. Differential expression analyses were conducted for multiple cancers using R software. Cox regression and survival analysis were employed to calculate correlations between ETV4 levels and survival outcomes in multiple cancers using the online tool Sangerbox. ETV4 expression was also compared with immunity, heterogeneity, stemness, mismatch repair genes, and DNA methylation among different cancers. ETV4 was found to be significantly upregulated in 28 tumors. Upregulation of ETV4 was associated with poor overall survival, progression free interval, disease-free-interval, and disease specific survival in several cancer types. Expression of ETV4 was also remarkably correlated with immune cell infiltration, tumor heterogeneity, mismatch repair gene expression, DNA methylation, and tumor stemness. Furthermore, ETV4 expression seemed to affect sensitivity to a number of anticancer drugs. These results suggest that ETV4 may be useful as a prognostic factor and therapeutic target.

Abstract 1006: Assessment of expression of microRNA-23b as a prognostic marker in cancer

Abstract Cancer is the major cause of death around the world. MiRNA-23b has been proposed to be expressed in various types of cancer. However, it’s prognostic role in several types of cancer has not been well identified. We conducted this meta-analysis to assess the associations between miRNA-23b expression and overall survival (OS) in various carcinoma. The current study presented the baseline characteristics and pooled survival results using a pooled hazard ratio (HR) with 95% confidence intervals (95% CI). Both Random and fixed effect models were conducted according to the heterogeneity of the analyzed. Then subgroup and publication bias analyses were executed. We identified a total sample size of 1589 in various carcinomas, including gastric (370), breast (203), ovarian (166), colorectal (206), renal (411), bladder (20), prostate (151) and lung cancer (62). The pooled HR of nine studies suggested that low miRNA-23b expression was obviously associated with worse OS (HR 3.2, 95% CI 2.26 to 4.53, P<0.001) with a low statistical heterogeneity index (I2=53%, P=0.03) in most of cancer types. On the other hand, the other three remaining studies (gastric and breast cancer) showed that miRNA-23b high expression was associated with reduced OS (HR 1.59, 95%CI 1.07 to 2.37, P<0.02) with no heterogeneity between the studies (I2=0%, P=0.38). All in all, our data showed that miRNA-23b was highly expressed in the plasma of breast and gastric cancer but was low expressed in most types of cancer. In addition, miRNA -23b expression is significantly associated with poor overall survival in several cancer types and might be considered as a potential prognostic marker. Citation Format: Ahmed Mahmoud Wadaaallah, Ahmed Samir Sultan. Assessment of expression of microRNA-23b as a prognostic marker in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1006.

Kynureninase Upregulation Is a Prominent Feature of NFR2-Activated Cancers and Is Associated with Tumor Immunosuppression and Poor Prognosis.

The nuclear factor erythroid 2-related factor 2 (NRF2) pathway is frequently activated in various cancer types. Aberrant activation of NRF2 in cancer is attributed to gain-of-function mutations in the NRF2-encoding gene NFE2L2 or a loss of function of its suppressor, Kelch-like ECH-associated protein 1 (KEAP1). NRF2 activation exerts pro-tumoral effects in part by altering cancer cell metabolism. Previously, we reported a novel mechanism of NRF2 tumoral immune suppression through the selective upregulation of the tryptophan-metabolizing enzyme kynureninase (KYNU) in lung adenocarcinoma. In the current study, we explored the relevance of NRF2-mediated KYNU upregulation across multiple cancer types. Specifically, using a gene expression dataset for 9801 tumors representing 32 cancer types from The Cancer Genome Atlas (TCGA), we demonstrated that elevated KYNU parallels increased gene-based signatures of NRF2-activation and that elevated tumoral KYNU mRNA expression is strongly associated with an immunosuppressive tumor microenvironment, marked by high expression of gene-based signatures of Tregs as well as the immune checkpoint blockade-related genes CD274 (PDL-1), PDCD1 (PD-1), and CTLA4, regardless of the cancer type. Cox proportional hazard models further revealed that increased tumoral KYNU gene expression was prognostic for poor overall survival in several cancer types, including thymoma, acute myeloid leukemia, low-grade glioma, kidney renal papillary cell carcinoma, stomach adenocarcinoma, and pancreatic ductal adenocarcinoma (PDAC). Using PDAC as a model system, we confirmed that siRNA-mediated knockdown of NRF2 reduced KYNU mRNA expression, whereas activation of NFE2L2 (the coding gene for NRF2) through either small-molecule agonists or siRNA-mediated knockdown of KEAP1 upregulated KYNU in PDAC cells. Metabolomic analyses of the conditioned medium from PDAC cell lines revealed elevated levels of KYNU-derived anthranilate, confirming that KYNU was enzymatically functional. Collectively, our study highlights the activation of the NRF2-KYNU axis as a multi-cancer phenomenon and supports the relevance of tumoral KYNU as a marker of tumor immunosuppression and as a prognostic marker for poor overall survival.

TGFβ1-Induced EMT in the MCF10A Mammary Epithelial Cell Line Model Is Executed Independently of SNAIL1 and ZEB1 but Relies on JUNB-Coordinated Transcriptional Regulation.

Epithelial-mesenchymal transition (EMT) fosters cancer cell invasion and metastasis, the main cause of cancer-related mortality. Growing evidence that SNAIL and ZEB transcription factors, typically portrayed as master regulators of EMT, may be dispensable for this process, led us to re-investigate its mechanistic underpinnings. For this, we used an unbiased computational approach that integrated time-resolved analyses of chromatin structure and differential gene expression, to predict transcriptional regulators of TGFβ1-inducible EMT in the MCF10A mammary epithelial cell line model. Bioinformatic analyses indicated comparatively minor contributions of SNAIL proteins and ZEB1 to TGFβ1-induced EMT, whereas the AP-1 subunit JUNB was anticipated to have a much larger impact. CRISPR/Cas9-mediated loss-of-function studies confirmed that TGFβ1-induced EMT proceeded independently of SNAIL proteins and ZEB1. In contrast, JUNB was necessary and sufficient for EMT in MCF10A cells, but not in A549 lung cancer cells, indicating cell-type-specificity of JUNB EMT-regulatory capacity. Nonetheless, the JUNB-dependence of EMT-associated transcriptional reprogramming in MCF10A cells allowed to define a gene expression signature which was regulated by TGFβ1 in diverse cellular backgrounds, showed positively correlated expression with TGFβ signaling in multiple cancer transcriptomes, and was predictive of patient survival in several cancer types. Altogether, our findings provide novel mechanistic insights into the context-dependent control of TGFβ1-driven EMT and thereby may lead to improved diagnostic and therapeutic options.

Statin drugs enhance responses to immune checkpoint blockade in head and neck cancer models

BackgroundAnti-PD-1 immune checkpoint blockade is approved for first-line treatment of recurrent/metastatic head and neck squamous cell carcinoma (HNSCC), but few patients respond. Statin drugs (HMG-CoA reductase inhibitors) are associated with...

An epithelial-mesenchymal plasticity signature identifies two novel LncRNAs with the opposite regulation.

The epithelial to mesenchymal transition (EMT) is crucial for cancer progression and chemoresistance. EMT is a dynamic process with multiple phases that change cell migration and invasion activity. We used pan-cancer expression data to find 14-LncRNAs that had a high correlation with the EMT markers VIM, CDH1, FN1, SNAI1, and SNAI2. The expression of 14 EMT-associated LncRNA, which also showed high cancer specificity, was used to calculate the pan-cancer EMT score. The EMT score was then applied to the 32 cancer types to classify them as epithelial, epithelial-mesenchymal, mesenchymal-epithelial, or mesenchymal tumors. We discovered that the EMT score is a poor prognostic predictor and that as tumor mesenchymal nature increased, patient survival decreased. We also showed that the cell of origin did not influence the EMT nature of tumors. Pathway analysis employing protein expression data revealed that the PI3K pathway is the most crucial in determining the EMTness of tumors. Further, we divided CCLE-cell lines into EMT classes and discovered that mesenchymal cells, which exhibited higher PI3K pathway activation, were more sensitive to PI3K inhibitors than epithelial cells. We identified Linc01615 as a mesenchymal LncRNA whose expression significantly correlated with survival in several cancer types. We showed that Linc01615 is regulated by the TGFβ-STAT3 pathway in a feedback loop. Knockdown of Linc01615 inhibited cell proliferation and migration by regulating the PI3K pathway and mesenchymal markers. We also identified RP4-568C11.4 as an epithelial cancer marker. We showed that knocking down RP4-568C11.4 decreased cell growth but not migration. In addition, we discovered that ESR1 regulates RP4-5681C11.4 in breast cancer. Taken together, we have developed a pan-cancer EMT signature. Also, we found two new LncRNAs that have different effects on cancer development and EMT.

Abstract 6109: Clonal relationship of B cells between tertiary lymphoid structures (TLSs) and tumor infiltrating lymphocytes (TILs) in advanced endometrial cancer

Abstract Objective: Tertiary lymphoid structures (TLSs) are known to be a marker of peripheral inflammation. While high densities of TLSs were reported to be associated with longer patient survival in several cancer types, there is no direct evidence where B cells in TLSs(TLBs) are derived from and whether these clones are consistent with tumor infiltrating B cells (TIBs), in endometrial cancer. Methods: We analyzed the pathological distribution of TLSs and TIBs in human endometrial cancer samples using immunohistochemistry of a series of B cell markers and evaluated the relationship with patients’ clinical outcomes. Additionally, we micro-dissected six pairs of tumor nests and their neighbor TLSs and analyzed the clonal consistency between TLBs and TIBs using the sequencing of complementarity-determining region (CDR) of B cell receptor (BCR). Results: In 104 patients with endometrial cancer, TLSs were detected in 81 patients (78%), and the absence of TLS was related to worse progression-free survival (PFS) (HR, 0.15, P <0.01). Among TLS-detected cases, the high number of TIBs was significantly associated with better PFS (P<0.05). BCR analyses in the six patients found that three patients with advanced stage had a unique B cell clones in common between TLBs and TIBs, while the other three patients with early stage did not have any common B cell clones. The frequency of common B cell clones in the former three patients were 10.3% (5250/51146 reads), 9.7% (1873/19369 reads) and 3.0% (1034/34618 reads). Conclusion: TLSs and TIBs are associated with better prognosis in endometrial cancer. Common B cell clones were found in the advanced stage cases, suggesting that B cells may have gradually acquired immunospecificity in TLSs. Citation Format: Haruka Suzuki, Junzo Hamanishi, Meng Qin, Masayo Ukita, Akihiko Ueda, Shunsuke Kawahara, Koji Yamanoi, Taito Miyamoto, Shiro Takamatsu, Mana Taki, Yoko Hosoe, Takashi Kobayashi, Ken Yamaguchi, Masaki Mandai. Clonal relationship of B cells between tertiary lymphoid structures (TLSs) and tumor infiltrating lymphocytes (TILs) in advanced endometrial cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6109.

Myoferlin targeting triggers mitophagy and primes ferroptosis in pancreatic cancer cells

Myoferlin, an emerging oncoprotein, has been associated with a low survival in several cancer types including pancreas ductal adenocarcinoma where it controls mitochondria structure and respiratory functions. Owing to the high susceptibility of KRAS-mutated cancer cells to iron-dependent cell death, ferroptosis, and to the high iron content in mitochondria, we investigated the relation existing between mitochondrial integrity and iron-dependent cell death. We discovered that myoferlin targeting with WJ460 pharmacological compound triggered mitophagy and ROS accumulation culminating with lipid peroxidation and apoptosis-independent cell death. WJ460 caused a reduction of the abundance of ferroptosis core regulators xc- cystine/glutamate transporter and GPX-4. Mitophagy inhibitor Mdivi1 and iron chelators inhibited the myoferlin-related ROS production and restored cell growth. Additionally, we reported a synergic effect between ferroptosis inducers, erastin and RSL3, and WJ460.

MiR-335 Restrains the Aggressive Phenotypes of Ovarian Cancer Cells by Inhibiting COL11A1.

Simple SummaryHigh collagen type XI alpha 1 (COL11A1) levels are associated with tumor progression, chemoresistance, and poor patient survival in several cancer types. We examined the role of miRNAs in regulating COL11A1 expression. This study highlighted the importance of miR-335 in downregulating COL11A1-mediated ovarian tumor progression, chemoresistance, and poor survival and suggested its potential application as a therapeutic target.High collagen type XI alpha 1 (COL11A1) levels are associated with tumor progression, chemoresistance, and poor patient survival in several cancer types. MicroRNAs (miRNAs) are dysregulated in multiple cancers, including epithelial ovarian carcinoma (EOC); however, the regulation of COL11A1 by miRNAs in EOC remains unclear. We examined the role of miRNAs in regulating COL11A1 expression. We identified miR-509 and miR-335 as the candidate miRNAs through an online database search. EOC cell treatment with miR-335 mimics abrogated COL11A1 expression and suppressed cell proliferation and invasion, besides increasing the sensitivity of EOC cells to cisplatin. Conversely, treatment with miR-335 inhibitors prompted cell growth/invasiveness and chemoresistance of EOC cells. miR-335 inhibited COL11A1 transcription, thus reducing the invasiveness and chemoresistance of EOC cells via the Ets-1/MMP3 and Akt/c/EBPβ/PDK1 axes, respectively. Furthermore, it did not directly regulate PDK1 but increased PDK1 ubiquitination and degradation through COL11A1 inhibition. In vivo findings highlighted significantly decreased miR-335 mRNA expressions in EOC samples. Furthermore, patients with low miR335 levels were susceptible to advanced-stage cancer, poor response to chemotherapy, and early relapse. This study highlighted the importance of miR-335 in downregulating COL11A1-mediated ovarian tumor progression, chemoresistance, and poor survival and suggested its potential application as a therapeutic target.

Prognostic impact of lymphopenia and neutrophil-lymphocyte ratio for patients with anal squamous cell carcinoma.

Outcomes after definitive chemoradiation for squamous cell carcinoma are generally favorable. However, biomarkers to further yield prognostic information are desired. Treatment-related lymphopenia as well as an elevated baseline neutrophil-lymphocyte ratio have been associated with worse survival in several cancer types. We evaluated absolute lymphocyte count and neutrophil-lymphocyte ratio at baseline and at treatment-related nadir in patients with anal cancer for associations with oncologic endpoints. We conducted a retrospective analysis of 428 consecutive patients with non-metastatic anal cancer treated with definitive, intensity-modulated radiation therapy-based chemoradiation. We analyzed absolute neutrophil and lymphocyte counts at several timepoints: pretreatment, weekly during treatment, and in the six weeks following treatment completion. Neutrophil-lymphocyte ratio was calculated at baseline and treatment-related nadir. We estimated oncologic endpoints using life tables and compared them using the log-rank test. We conducted univariate and multivariable time-to-event analyses using Cox proportional hazards. Median absolute lymphocyte count at baseline and nadir were 1.80 [interquartile range (IQR), 1.45-2.32] k/µL and 0.26 (IQR, 0.18-0.36) k/µL, respectively, and 31% developed treatment-related grade 4 lymphopenia. Median neutrophil-lymphocyte ratio at baseline and nadir were 2.34 (IQR, 1.68-3.30) and 8.80 (IQR, 5.86-12.68), respectively. Estimates of overall survival, local failure-free survival, distant metastasis-free survival (DMFS), and freedom from colostomy at 5 years were 87%, 86%, 82%, and 88%, respectively. Baseline and nadir absolute lymphocyte count were not associated with selected outcomes on univariate analysis. On multivariable analysis, factors independently associated with death included T3-T4 disease, HIV-positive status, treatment break, and baseline neutrophil-lymphocyte ratio >3. Baseline neutrophil-lymphocyte ratio showed a trend toward association with distant progression or death (P=0.07). The 5-year overall survival estimates for patients with baseline neutrophil-lymphocyte ratios ≤3 and >3 were 92.3% and 80.6%, respectively. Lymphopenia during and after chemoradiation for anal cancer is common but does not appear to be associated with worse survival, recurrence, or metastases. However, elevated baseline neutrophil-lymphocyte ratio was independently associated with overall survival, local recurrence-free survival, and DMFS. Further studies are needed to determine the clinical utility of baseline neutrophil-lymphocyte ratio to guide treatment and follow-up.

Anti-PD-1/Anti-PD-L1 Drugs and Radiation Therapy: Combinations and Optimization Strategies.

Simple SummaryAlthough immune checkpoint blockade has yielded unprecedented and durable responses in cancer patients, the efficacy of this treatment remains limited. Radiation therapy can induce immunogenic cell death that contributes to the local efficacy of irradiation. However, radiation-induced systemic responses are scarce. Studies combining radiation with checkpoint inhibitors suggest a synergistic potential of this strategy. In this review, we focused on parameters that can be optimized to enhance the anti-tumor immune response that results from this association, in order to achieve data on dose, fractionation, target volume, lymph nodes sparing, radiation particles, and other immunomodulatory agents. These factors should be considered in future trials for better clinical outcomes. To this end, we discussed the main preclinical and clinical data available to optimize the efficacy of the treatment combination.Immune checkpoint inhibitors have been associated with long-term complete responses leading to improved overall survival in several cancer types. However, these novel immunotherapies are only effective in a small proportion of patients, and therapeutic resistance represents a major limitation in clinical practice. As with chemotherapy, there is substantial evidence that radiation therapy promotes anti-tumor immune responses that can enhance systemic responses to immune checkpoint inhibitors. In this review, we discuss the main preclinical and clinical evidence on strategies that can lead to an enhanced response to PD-1/PD-L1 blockade in combination with radiation therapy. We focused on central issues in optimizing radiation therapy, such as the optimal dose and fractionation for improving the therapeutic ratio, as well as the impact on immune and clinical responses of dose rate, target volume, lymph nodes irradiation, and type of radiation particle. We explored the addition of a third immunomodulatory agent to the combination such as other checkpoint inhibitors, chemotherapy, and treatment targeting the tumor microenvironment components. The strategies described in this review provide a lead for future clinical trials.

Immunoscore Signatures in Surgical Specimens and Tumor-Infiltrating Lymphocytes in Pretreatment Biopsy Predict Treatment Efficacy and Survival in Esophageal Cancer.

Tumor-infiltrating lymphocytes (TILs) have long been recognized as playing an important role in tumor immune microenvironment. Lately, the Immunoscore (IS) has been proposed as a new method of quantifying the number of TILs in association with patient survival in several cancer types. In 300 preoperatively untreated esophageal cancer (EC) patients who underwent curative resection at two different institutes, immunohistochemical staining using CD3 and CD8 antibodies was performed to evaluate IS, as objectively scored by auto-counted TILs in the tumor core and invasive margin. In addition, in pre-neoadjuvant chemotherapy (pre-NAC) endoscopic biopsies of a different cohort of 146 EC patients who received NAC, CD3, and CD8 were immunostained to evaluate TIL density. In all cases, the IS-high (score 3-4) group tended to have better survival [5-year overall survival (OS) of the IS-high vs low group: 77.6 vs 65.8%, P = 0.0722] than the IS-low (score 1-2) group. This trend was more remarkable in cStage II-IV patients (70.2 vs 54.5%, P = 0.0208) and multivariate analysis of OS further identified IS (hazard ratio 2.07, P = 0.0043) to be an independent prognostic variable. In preNAC biopsies, NAC-responders had higher densities than non-responders of both CD3 + ( P = 0.0106) and CD8 + cells ( P = 0.0729) and, particularly CD3 + cell density was found to be an independent prognostic factor (hazard ratio 1.75, P = 0.0169). The IS signature in surgical specimens and TIL density in preNAC- biopsies could be predictive markers of clinical outcomes in EC patients.

Breast cancer resistance mechanisms: challenges to immunotherapy.

The clinical implementation of immunotherapy has profoundly transformed cancer treatment. Targeting the immune system to mount anti-tumor responses can elicit a systemically durable response. Employing immune checkpoint blockade (ICB) has suppressed tumor growth and vastly improved patient overall and progression-free survival in several cancer types, most notably melanoma and non-small cell lung carcinoma. Despite widescale clinical success, ICB response is heterogeneously efficacious across tumor types. Many cancers, including breast cancer, are frequently refractory to ICB. In this review, we will discuss the challenges facing immunotherapy success and address the underlying mechanisms responsible for primary and acquired breast cancer resistance to immunotherapy. Even in initially ICB-responsive tumors, many acquire resistance due to tumor-specific alterations, loss of tumor-specific antigens, and extrinsic mechanisms that reshape the immune landscape within the tumor microenvironment (TME). The tumor immune interaction circumvents the benefits of immunotherapy; tumors rewire the tumor-suppressive functions of activated immune cells within their stroma to propagate tumor growth and progression. The breast cancer immune TME is complex and the mechanisms driving resistance to ICB are multifaceted. Continued study in both preclinical models and clinical trials should help elucidate these mechanisms so they can be targeted to benefit more breast cancer patients.

MET Expression and Cancer Stem Cell Networks Impact Outcome in High-Grade Serous Ovarian Cancer.

Overexpression of the receptor tyrosine kinase MET has been linked to poor survival in several cancer types, and MET has been suggested to interact with stem cell networks. In vitro studies have further suggested a possible benefit of a combined treatment using PARP and MET inhibitors. We used a tissue microarray (TMA) with 130 samples of advanced-stage high-grade serous fallopian tube/ovarian cancer (HGSC) to investigate the prognostic value of MET protein expression alone and in combination with the stem cell factor SOX2. The possible synergistic effects of a PARP and MET inhibitor treatment were evaluated in two cell lines with BRCA1 or BRCA2 deficiency and in their BRCA1/2-proficient counterparts. Patients with tumors positive for MET had worse overall survival (log-rank test, p = 0.015) compared to patients with MET-negative tumors. The prognostic role of MET was even more prominent in the subgroup of patients with SOX2-negative tumors (p = 0.0081). No synergistic effects of the combined treatment with PARP and MET inhibitors were found in the cell lines examined. We conclude that MET expression could be used as a marker for OS in HGSC and that stemness should be taken into consideration when evaluating the mechanisms of this effect.

Large scale analysis of smoking-induced changes in the tumor immune microenvironment

Abstract Here, we expanded the recent knowledge on the immune landscape of cancer by performing a comparative analysis of tobacco smoking-induced changes in the populations of major immune cell types between smokers and never-smokers (people who have never smoked). To investigate the immune response of smokers and never-smokers, the relative abundance of immune cell types was calculated by both CIBERSORT and xCell based on TCGA RNA-seq data. We further validated the findings using publicly available bulk RNA-seq and single-cell RNA-seq data from cohorts of cancer patients other than TCGA cohort. We showed statistically significant smoking-induced changes in immune cell populations in all studied cancers. The increase in plasma cell populations and the changes in the ratio of activated to resting immune cell types were the most consistent features distinguishing smokers and never-smokers across different cancers, with both being correlated with survival outcomes. We found that the tobacco-induced changes in populations of immune cells were not as marked in cancers of tissues that are not directly exposed to smoke as in lung cancers and head and neck cancer (LUAD, LUSC, and HNSC). However, the significant differences in survival in several cancer types suggest that even a small shift in the frequency of immune cell types might result in adverse outcomes. We also showed that smoking-induced changes in the patterns of immune cell populations and their correlations to survival outcomes are stronger in female smokers than in males. In general, the findings of this study suggest that certain immune cell types could potentially be used as common prognostic markers and therapeutic targets for active smoker patients.

XPO7 is a tumor suppressor regulating p21CIP1-dependent senescence.

Senescence is a key barrier to neoplastic transformation. To identify senescence regulators relevant to cancer, we screened a genome-wide shRNA library. Here, we describe exportin 7 (XPO7) as a novel regulator of senescence and validate its function in telomere-induced, replicative, and oncogene-induced senescence (OIS). XPO7 is a bidirectional transporter that regulates the nuclear-cytoplasmic shuttling of a broad range of substrates. Depletion of XPO7 results in reduced levels of TCF3 and an impaired induction of the cyclin-dependent kinase inhibitor p21CIP1 during OIS. Deletion of XPO7 correlates with poorer overall survival in several cancer types. Moreover, depletion of XPO7 alleviated OIS and increased tumor formation in a mouse model of liver cancer. Our results suggest that XPO7 is a novel tumor suppressor that regulates p21CIP1 expression to control senescence and tumorigenesis.